Antipsychotics combination therapy

Freudenreich 0, Goff DC Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002 106 323.[PMID 12366465]... 

Combination therapies (e.g., lithium plus valproate or carbamazepine lithium or valproate plus an atypical antipsychotic) may provide better acute response and prevention of relapse and recurrence than monotherapy in some bipolar patients, especially those with mixed states or rapid cycling. 

Psychotically depressed individuals generally require either ECT or combination therapy with an antidepressant and an antipsychotic agent. 

Lithium (Eskaiith, Lithobid). Before the recent proliferation of atypical antipsychotics, lithium was tried as an alternative for schizophrenia. By and large, this represented another effort to circumvent the risk of tardive dyskinesia. It is not effective either as monotherapy or as combination therapy with antipsychotics in schizophrenia. 

Although the data are fairly convincing that TCAs alone are not as efficacious in PMD as they are in NPMD, the data are equally convincing that combination therapy of a TCA with an antipsychotic is an effective strategy for PMD. 

Several small, open-label studies have supported TCA/antipsychotic combinations in the treatment of PMD. Minter and Mandel [1979) studied 54 inpatients with PMD who were treated openly with either TCAs alone, TCAs and antipsychotic combination, antipsychotics alone, or electroconvulsive therapy [ECT] in treatment failures. Although only 3 of 11 patients treated with TCAs alone responded, 16 of 16 patients treated with the combination of a TCA and an antipsychotic responded. Interestingly, 14 of 15 patients treated with antipsychotic drugs alone also responded, which is contrary to findings in other studies [Spiker et al. 1985). Several other open-label studies have confirmed the utility of the combination treatment for PMD [Charney and Nelson 1981 Frances et al. 1981), but few controlled studies have been completed. 

To date, only one study has been completed with an antidepressant other than a TCA combined with an antipsychotic in the treatment of PMD. Rothschild and colleagues (1993) investigated the efficacy of fluoxetine and perphenazine in the treatment of PMD and found that approximately 73% of 30 patients who met DSM-III-R (American Psychiatric Association 1987) criteria for major depression with psychotic features had at least a 50% reduction on their Hamilton Rating Scale for Depression scores over 5 weeks. Furthermore, the combination of fluoxetine and perphenazine appeared to be better tolerated than the combination of TCAs with antipsychotics. Although there is no evidence that monotherapy with an antidepressant other than amoxapine is efficacious, the combination therapy with many antidepressants other than the TCAs may prove useful. 

Certain disorders may require combined therapy. For example, SA-bipolar type may best respond to the addition of mood stabilizers, and BZDs may be useful adjuncts for agitated psychoses. Conversely, some mood disorders may require augmentation with antipsychotics (e.g., delusional depression). Unfortunately, except for schizophrenia, most other psychotic conditions have not been systematically studied to determine the optimal use of these agents. 

In this context, there is anecdotal clinical data indicating that risperidone and clozapine can be overlapped or used concomitantly with beneficial results and no serious adverse reactions (99,100, 101 and 102). This strategy has been used successfully for residual positive symptoms during clozapine therapy and in patients who relapsed when a neuroleptic was withdrawn from combined therapy with clozapine. Indeed, up to 60% of clozapine-treated patients receive additional medication, including a second antipsychotic. 

Another area of continuing use of conventional antipsychotics is for the noncom-pliant patient who may require monthly injections of a depot antipsychotic. No atypical antipsychotic is yet available for depot administration, although such formulations are under development. Otherwise, most clinicians generally try several different atypical antipsychotics before resorting to a trial of clozapine (with its encumbrance of weekly or biweekly blood counts), conventional antipsychotics, or various combination therapies of atypical antipsychotics with other agents (Fig. 11 — 52 second- and third-line treatments). 

There are few controlled studies in children and adolescents with bipolar disorder, thus little is known about the long-term efficacy and safety of specific agents or for combination therapies in this population. The only published guidehnes for children and adolescents are the Practice Parameters for the Assessment and Treatment of Children and Adolescents with Bipolar Disorder by the American Academy of Child and Adolescent Psychiatry, and a proposed treatment algorithm for pediatric bipolar disorder. A more complete review of using mood stabilizers and antipsychotics in children and adolescents can be found elsewhere. ... 

Alternative atypical antipsychotics (for psychosis) or combination therapies Carbamazepine or oxcarbazepine induce liver enzymes and may affect the metabolism and blood levels of concomitant medications lithium, antipsychotics, and benzodiazepines increase the risk of adverse effects and cognitive impairment... 

This syndrome is a combination of symptomatic effects produced by antipsychotic drug therapy. Symptoms and signs include hyperpyrexia, muscle rigidity, altered mental status (e.g., catatonia) and cardiovascular instability (e.g., unstable heart rate and blood pressure). Acute renal failure may ultimately occur. Diagnostic signs include elevated creatine phosphokinase (CPK) and myoglobinuria. 

There is, however, a unique risk in the bipolar form that antidepressant treatment may trigger a switch into mania. This may occur either as the natural outcome of recovery from depression or as a pharmacological effect of the drug. Particular antidepressants (the selective serotonin reuptake inhibitors) seem less liable to induce the switch into mania than other antidepressants or electroconvulsive therapy. Treatment for mania consists initially of antipsychotic medication, for instance the widely used haloperidol, often combined with other less specific sedative medication such as the benzodiazepines (lorazepam intramuscularly or diazepam orally). The manic state will usually begin to subside within hours and this improvement develops further over the next 2 weeks. If the patient remains disturbed with manic symptoms, additional treatment with a mood stabilizer may help. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Conventional antipsychotic drugs such as chlorpromazine and haloperidol have long been used in the treatment of acute mania. More recently, atypical antipsychotic drugs including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasi-done have been approved for the treatment of bipolar mania or mixed mood episodes as monotherapy or in combination with mood-stabilizing drugs.25 Aripiprazole and olanzapine are also approved for maintenance therapy. The combination of olanzapine and fluoxetine is approved for treatment of bipolar depression. Quetiapine is approved for treatment of... 

Combining lithium with typical antipsychotics may cause neurotoxicity (e.g., delirium, cerebellar dysfunction, extrapyramidal symptoms). Lithium should be withdrawn and discontinued at least 2 days before electroconvulsive therapy. 

Augmentation therapy involves the addition of a non-antipsychotic drug to an antipsychotic in a poorly responsive patient, while combination treatment involves using two antipsychotics simultaneously. 

To date, only one antidepressant, amoxapine, has proven effective in the treatment of PMD as the sole therapy. Amoxapine is a chemical congener of the antipsychotic drug loxapine, so it possesses both dopamine-blocking and monoamine-enhancing properties. One double-blind study has confirmed that amoxapine appears to be as effective as the combination of a TCA and an antipsychotic. R. F. Anton and Burch [1990] randomly selected 46 inpatients with psychotic depression to either amoxapine [to 400 mg/day] or ami-... 

---